Summary of work: In the past year significant progress has been made in our studies of short-term CR. Recently we have demonstrated that it is possible to initiate CR in older monkeys (greater than 18 years)to produce many potentially beneficial effects even when CR is begun at this advanced age. For example, CR reduced fasting insulin and to a lesser degree triglyceride levels. Consistent with findings in rodent models, we have also shown that key metabolic enzymes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase, PEPCK), glycolysis (pyruvate kinase, PK) and ammonia detoxification (carbamyl phosphate synthase I, CPSI) are also altered in these old monkeys on short-term CR. Lastly, we have shown that triiodothyronine (T3), a major endocrine regulator of metabolism, is reduced in younger and older male rhesus monkeys during short-term CR. During the past year we also completed a preliminary analysis of the effects of CR on morbidity and mortality in our longitudinal study in primates. We examined the incidence of disease in several major categories in control and CR rhesus monkeys. We observed that five control monkeys had been diagnosed with either cardiovascular disease or diabetes compared to only one in the CR group. Similarly, five controls were found to have a malignant neoplasia in the control group, compared to one CR monkey. Lastly, four female controls have been diagnosed with endometriosis as compared to only one monkey in the CR group. Consistent with these observations, the number of deaths in these broad disease categories is also apparently reduced by CR. These preliminary findings have not been subjected to rigorous statistical analyses due to the relatively small numbers of disease occurrences and deaths but do suggest that CR may reduce morbidity in primates. We also studied the effects of CR on age-related bone loss and reproductive indices in male and female monkeys. Male monkeys on CR exhibited a slight, site-specific (radius only) reduction in bone mass that was not observed in females on CR. Biochemical studies revealed no abnormalities in markers of bone turnover, calcium homeostasis or reproductive hormones. Menstrual cycling in females was unaffected. These studies suggest that CR does not disrupt normal skeletal metabolism and that effects in male monkeys may be related to changes in bone remodeling due to altered body composition. Further longitudinal studies are necessary to determine if CR alters the onset of menopause and the acceleration of bone loss that accompanies cessation of reproductive cycling in females.